OBJECTIVE: To characterize the long-term clinical course of children with hematologic non-criteria manifestations and persistent antiphospholipid antibodies (aPL), and to identify predictors of progression to antiphospholipid syndrome (APS) and/or systemic lupus erythematosus (SLE). METHODS: We conducted a prospective cohort study of children (<18 years) with persistent aPL positivity and hematologic involvement (thrombocytopenia, autoimmune hemolytic anemia [AIHA], or Evans syndrome) followed at a tertiary pediatric rheumatology center between 1995 and 2024, with follow-up extending into adulthood. Progression to clinically classifiable APS and/or SLE was the primary endpoint. Kaplan-Meier and Cox proportional hazards models evaluated predictors at presentation and in complementary time-dependent analyses. RESULTS: Among 42 enrolled children, 40 were evaluable, of whom 11 (27.5%) progressed to APS and/or SLE. Evans syndrome at presentation was associated with the highest hazard of progression compared with isolated thrombocytopenia (HR 6.21, 95% CI 1.46-26.41). In time-dependent analyses, Evans syndrome emerging during follow-up remained associated with progression. Isolated thrombocytopenia showed the lowest risk, whereas AIHA represented an intermediate state that did not independently predict progression. Lupus anticoagulant was nearly universal, and broader high-risk aPL profiles were more common among progressors but were not statistically significant. CONCLUSION: In children with persistent aPL positivity, Evans syndrome was the hematologic phenotype most strongly associated with progression to APS and/or SLE, whereas isolated thrombocytopenia followed a largely indolent course. Evolving hematologic phenotypes may improve risk stratification and inform long-term monitoring strategies within the APS-SLE spectrum.
Objective The APS ACTION Registry was created to study long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. The objectives of this study were to examine the ethnoracial differences in clinical and laboratory characteristics of aPL-positive patients with no other systemic autoimmune rheumatic diseases (SARDs). Methods A web-based data capture system stores patient demographics and aPL-related medical history. Inclusion criteria are positive aPL results, based on the revised Sapporo APS classification criteria, tested at least twice within one year prior to enrollment. For this cross-sectional analysis of the baseline data, demographic, clinical, and laboratory characteristics of registry patients were analyzed based on self-reported ethnorace (White, Latin American Mestizo [LAM], Asian, and Black). Results 728 patients with no history of other SARD (78% with APS classification) were included in the analysis. The ethnoracial distribution was 516 (78%) White, 82 (12%) LAM, 49 (7%) Asian, and 13 (2%) Black. Based on ethnoracial comparisons: (a) there were less females among White patients; (b) livedo reticularis/racemosa was more frequent in LAM patients; and (c) triple aPL positivity was more frequent in Whites, while isolated lupus anticoagulant positivity was more common in LAM patients. Conclusion In our international registry of persistently aPL-positive patients with or without APS classification, Blacks were the least frequently (2%) reported ethnoracial group. No major ethnoracial differences were found in the aPL-related clinical manifestations. Our analysis highlights the need for further investigation into the genetic and social determinants impacting the clinical and serologic phenotypes of aPL-positive patients across diverse populations.
Significant titers of antiphospholipid antibodies (aPL) vary across populations, but the clinically relevant threshold for diagnosing antiphospholipid syndrome (APS) in South Indians is unknown. This study aimed to determine population-specific aPL cut-off values in South India. We conducted a cross-sectional validity study at a tertiary care hospital in Kerala, India. Blood samples from 125 healthy individuals were analyzed to establish cut-off values for anticardiolipin (aCL) and anti-beta-2-glycoprotein I (anti-β2GPI) antibodies (IgG/IgM) using ELISA. Cut-off values were calculated using both 95th and 99th percentile methods (before and after excluding outliers) and receiver operating characteristic (ROC) curve analysis. Validity was evaluated by comparing 118 patients with APS criteria manifestations to 81 patients without such manifestations. aPL values showed a non-parametric distribution. The 99th percentile cut-offs before excluding outliers were 17.3 GPL (IgG aCL), 12.4 MPL (IgM aCL), 41.5 SGU (IgG anti-β2GPI), and 23.4 SMU (IgM anti-β2GPI). After excluding outliers, 99th percentile values were 2.6 GPL, 12.4 MPL, 16.7 SGU, and 15.7 SMU, respectively. The 99th percentile cut-offs had superior specificity when outliers were not excluded, while ROC-derived cutoff values yielded a greater Youden Index compared to the other cutoff’s, in all aPLs. This is the first study to define aPL reference values for South Indians, revealing substantial differences from manufacturer recommendations, Modified Sapporo criteria, and international data. Region-specific aPL thresholds are essential for accurate APS diagnosis. Standardizing cut-off calculation methods is recommended to improve diagnostic accuracy and interpretation across populations.
Objective To evaluate the sensitivity of the 2023 ACR/EULAR classification criteria for antiphospholipid syndrome (APS) in a real‐world cohort of women diagnosed with primary obstetric APS (oAPS), and to assess their ability to identify patients at risk of future pregnancy complications. Methods We conducted a multicenter retrospective study on women diagnosed with primary oAPS by expert rheumatologists between 2006 and 2023 in two Italian rheumatology centers. All patients were retrospectively classified using both the 2006 Sydney and the 2023 ACR/EULAR classification criteria. Follow‐up at 1 and 5 years after clinical diagnosis was analyzed to identify new obstetric events and assess associations with baseline classification status. Results Our cohort included 122 women. At baseline, 75.4% of patients fulfilled the Sydney criteria, and 23% met the 2023 ACR/EULAR criteria. The main reasons for exclusion under the 2023 ACR/EULAR criteria were insufficient clinical score due to isolated fetal losses (56.4%), insufficient laboratory score due to isolated IgM aPL positivity (4.3%), or a combination of both (5.3%). During five years of follow‐up, more than one‐quarter of the patients who became pregnant experienced new obstetric events. The majority of these cases did not fulfill the 2023 ACR/EULAR criteria. Conclusion The 2023 ACR/EULAR classification criteria demonstrate low sensitivity (23%) in women with primary oAPS and fail to identify those at risk of future events. These findings underscore the need for cautious clinical judgment in managing oAPS: misuse of these criteria may result in undertreatment and increase the risk of recurrent obstetric complications.
Antiphospholipid syndrome (APS) lacks systematic comparative evidence for the diagnostic performance of its three classification criteria, namely the 1999 Sapporo criteria, 2006 Revised criteria, and 2023 ACR criteria. This study aimed to comprehensively evaluate and compare the performance of the three criteria via a systematic review and network meta-analysis, providing an evidence-based basis for their clinical and research application. Following the PRISMA-NMA statement, we systematically searched PubMed, Embase, Cochrane Library, and Web of Science from inception to October 13, 2025, for studies evaluating the performance of the three APS classification criteria. Two reviewers independently performed study selection, data extraction, and quality assessment using the QUADAS-2 tool. Pairwise meta-analysis was conducted with Stata 15.0 to calculate the relative sensitivity and specificity. Network meta-analysis was performed using RStudio 4.3.0 to analyze sensitivity, specificity, DOR, and S index, and rank the diagnostic performance of the three criteria. Heterogeneity and publication bias were assessed using the I² index and Deeks' funnel plot asymmetry test, respectively. A total of 7 eligible studies involving 8 research cohorts (2,214 APS patients, 3,908 subjects) were included. In the direct pairwise meta-analysis of the 2006 Revised criteria versus the 2023 ACR criteria, the 2023 ACR criteria showed significantly lower sensitivity (relative sensitivity 0.80; 95% CI: 0.72-0.89; P < 0.01) and significantly higher specificity (relative specificity 1.06; 95% CI: 1.05-1.08; P < 0.01) compared with the 2006 Revised criteria. Network meta-analysis indicated that the 2006 Revised criteria had the highest sensitivity (0.86, 95% CI: 0.83-0.88) and S index (1.92, 95% CI: 0.33-3.00) among the three; the 2023 ACR criteria had the highest specificity (0.98, 95% CI: 0.97-0.98) and DOR (114.66, 95% CI: 75.46-168.19). The 1999 Sapporo criteria have limited clinical
This review summarizes the current evidence on the impact of isolated antiphospholipid antibody positivity (IAAP) on pregnancy outcomes. It analyzes risk differentials across antibody subtypes, synthesizes the underlying pathophysiological mechanisms, and reviews existing treatment strategies to inform clinical practice. A comprehensive review was conducted. Data were retrieved and analyzed from relevant observational, cohort, and randomized controlled trials, both domestically and internationally, focusing on clinical outcomes, risk stratification, pathogenic mechanisms, and the management of IAAP. Positive antiphospholipid antibodies alone constitute a risk factor for adverse pregnancy outcomes. The pathological mechanisms linking IAAP to adverse outcomes involve multiple processes, including thrombosis, trophoblast dysfunction, and complement activation. Clinical management should involve risk stratification based on antibody profiles. For high-risk patients, a combination therapy of low-molecular-weight heparin and aspirin is recommended, with hydroxychloroquine as a potential adjuvant. Standardization of antibody testing and optimal timing for dynamic monitoring remain areas needing improvement. IAAP is associated with an increased risk of adverse pregnancy outcomes. Further research is needed to determine whether the presence of these antibodies may contribute to the development of autoimmune disease. Future research should focus on developing precise risk-stratification models that integrate antibody type, titer, and clinical features. Prospective studies are warranted to establish individualized monitoring and intervention protocols, ultimately contributing to an evidence-based clinical consensus.
Non-criteria antiphospholipid antibodies (aPLs) may be associated with adverse obstetric outcomes in patients who do not meet conventional antiphospholipid syndrome (APS) classification criteria. Their clinical relevance in fetal growth restriction (FGR) remains incompletely defined. This retrospective cohort study included 104 pregnant women with FGR or related adverse obstetric presentations who underwent comprehensive testing for 26 solid-phase aPL markers, together with lupus anticoagulant assessment. Criteria-aPL positivity was defined as positivity for lupus anticoagulant, anticardiolipin IgG/IgM, or anti-β2-glycoprotein I IgG/IgM. IgA aCL and IgA anti-β2GPI were measured as exploratory markers but were not included in criteria-aPL classification. Patients were categorized according to criteria and non-criteria aPL status. Hierarchical clustering was performed using the 26 solid-phase aPL markers. Continuous outcomes were compared using Kruskal-Wallis or Wilcoxon rank-sum tests, and categorical outcomes using Fisher's exact test. Birth-weight analyses were restricted to live births. Treatment status was assessed using Fisher's exact test with Haldane-Anscombe correction for odds ratio estimation when appropriate. Among live births, gestational age at delivery and birth weight differed significantly across antibody-profile groups. Patients positive for both criteria and non-criteria aPLs had the lowest median gestational age and birth weight, 36.43 weeks (IQR, 34.57-38.00) and 2.15 kg (IQR, 1.88-2.55), respectively. The overall differences were significant for gestational age and birth weight, with p values of 0.010 and 0.007. Hierarchical clustering identified three aPL phenotypes with significant differences in gestational age and birth weight among live births, with p values of 0.011 and 0.018, respectively. In the criteria-aPL-negative and chromosomally normal subgroup, non-criteria aPL positivity was mainly driven by IgM aPE, IgM aPS/PT, and aANXA5. Treatment status was strongly associated with pregnancy outcome. Comprehensive profiling of non-criteria aPLs may provide additional risk-stratification information in
Adrenal involvement is a rare but potentially severe immunothrombotic manifestation of antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE)-spectrum disease. Because the term adrenal crisis should be reserved for patients with acute adrenal insufficiency accompanied by hypotension or shock, this review distinguishes adrenal vascular injury, adrenal insufficiency, and strict adrenal crisis. We performed a systematic review and individual-patient pooled analysis of published cases of APS/SLE-spectrum adrenal involvement through March 31, 2026. The initial database search was performed from inception to February 10, 2026 and was updated through March 31, 2026. The study selection followed PRISMA 2020 principles, and the protocol was registered in PROSPERO (CRD420261298329). Published patients were harmonized for diagnosis stratum, precipitating trigger, adrenal imaging phenotype, adrenal insufficiency chronology, immunologic profile, thrombotic burden, treatment/follow-up variables, CAPS presentation context, and outcomes. A total of 103 studies comprising 155 published patients were included; 143 entered the main analysis set. The median age was 43.8 years, 49.0% were female, and primary APS accounted for 67.1% of the main cohort. Hemorrhage-dominant adrenal injury was the leading imaging phenotype (66.9%), bilateral adrenal involvement was highly prevalent (86.3% of informative cases), and adrenal insufficiency was the first manifestation in 73.6% of informative cases. Among codable main-analysis cases, hypotension was documented in 60/125 (48.0%), strict adrenal crisis in 64/124 (51.6%), hyponatremia in 47/142 (33.1%), and hyperkalemia in 57/134 (42.5%). CAPS was treated as a presentation/severity context rather than as a downstream consequence and was reported in 59.8% of evaluable patients. Adrenal involvement in APS and lupus-spectrum disease is a heterogeneous but clinically recognizable high-risk phenotype characterized by bilateral adrenal injury, hemorrhagic predominance, frequent sentinel presentation as adrenal insufficiency, and substantial CAPS burden. Careful terminology helps separate
Rheumatic and musculoskeletal diseases (RMDs) confer an increased cardiovascular risk beyond traditional factors, with peripheral artery disease (PAD) being an important source of morbidity and disability in these patients. This review summarizes current evidence on PAD across RMDs, including rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis, polymyalgia rheumatica, psoriatic arthritis, and primary Sjögren's syndrome. Physiopathological mechanisms involved include persistent inflammation, immune dysregulation, and the presence of pathogenic autoantibodies. Protective humoral responses have also been linked to reduced CV risk and may serve as future biomarkers. Clinical studies reveal variable PAD prevalence across diseases but consistent high underdiagnosis. Optimal management requires aggressive CV risk control, including lipid-lowering, immunomodulatory, and biologic therapies. This review underscores PAD as a distinct and clinically relevant manifestation of systemic autoimmunity, calling for targeted screening and prevention strategies in rheumatic populations.
Obstetric antiphospholipid syndrome (OAPS) is a complex autoimmune disorder that significantly compromises pregnancy, manifesting as recurrent miscarriage, stillbirth, placental insufficiency, and preeclampsia. Its increasing prevalence underscores the pressing need to elucidate its multifaceted pathogenic mechanisms to improve maternal and fetal outcomes. While traditionally attributed to thrombosis driven by antiphospholipid antibodies (aPL), emerging evidence indicates that OAPS can disrupt placental perfusion, impair trophoblast proliferation and invasion, and compromise placental angiogenesis even in the absence of overt thrombotic events. Beyond direct effects on trophoblasts and vascular remodeling, aPLs profoundly perturb the immune milieu at the maternal-fetal interface, encompassing complement activation, excessive formation of neutrophil extracellular traps (NETs), dysfunction of decidual natural killer cells and macrophages, and dysregulated B cell responses. These immune-mediated alterations collectively establish a sustained pro-inflammatory environment that undermines placental development and predisposes to adverse pregnancy outcomes. This review provides a comprehensive synthesis of the immunopathogenic mechanisms of OAPS that extend beyond thrombosis, and emphasizes the intricate crosstalk between immune cells and the complement-NET axis. A deeper understanding of these immune-mediated pathways may inform the development of targeted therapeutic strategies to optimize maternal and fetal outcomes in affected pregnancies.
To develop and validate a European Alliance of Associations for Rheumatology (EULAR) disease activity score in antiphospholipid syndrome (EAPSDAS). Twenty-four Task Force members and an international group of 53 antiphospholipid syndrome (APS) experts/collaborators, 65 patients with primary APS, and 21 healthcare professionals participated. EAPSDAS development proceeded in 4 phases: (i) item generation using a systematic literature review and 2 surveys; (ii) item reduction by rating items on their importance to be included in EAPSDAS and using Delphi methodology; (iii) item scoring based on real-world clinical vignettes and using as criterion standard the physician global assessment (PhysGA); and (iv) validation. One hundred seventy items representing APS activity were generated, and 140 deduplicated candidate items were rated by participants. Using a ≥75% vote threshold and Delphi consensus among Task Force members, 24 items were included in the EAPSDAS thrombotic/microvascular/nonthrombotic (TMN) scale and 6 in the obstetric scale. Item scoring was based on ratings of 3 versions of 60 vignettes with new/worsening manifestations (30 single TMN or obstetric manifestations, 26 combinations of 2 TMN manifestations, 2 inactive cases, 2 testing cases) by physicians. Item scores were calculated as the adjusted mean PhysGA in linear regression analysis. A 1-month time frame was defined for the TMN scale and the entire pregnancy for the obstetric scale. Scores for stable or improved TMN manifestations were also included. High face and content validity, construct validity (internal/external standard), and reliability were demonstrated using real-world clinical vignettes. Using data-driven and consensus methodology, EAPSDAS was developed and initial validation was performed. Further validation in prospective studies is warranted.
An international multi-disciplinary initiative resulted in the development of 2023 ACR/EULAR Antiphospholipid Syndrome (APS) Classification Criteria to identify patients with high likelihood of APS for research. Phase I/II resulted in 27 candidate criteria organized into six clinical and laboratory domains. Here, we summarize early Phase III efforts to better define and structure candidate criteria within clinical and laboratory domains. Using comprehensive literature reviews and expert consensus, domain subcommittees developed definitions for candidate criteria. Prevalence information was incorporated when available. Definitions were finalized and approved by the Steering Committee for future use during real-world case collection (derivation cohort), multi-criteria decision analysis, and validation. Clinical domain items defined were: (a) macrovascular thrombosis (venous thromboembolism including superficial venous thrombosis, arterial thrombosis, and transient ischemic attack) and associated provoking risk factors; (b) microvascular disease (livedo racemosa, livedoid vasculopathy, antiphospholipid-antibody-nephropathy, diffuse alveolar hemorrhage, cardiac microthrombosis, adrenal hemorrhage, and acute ischemic encephalopathy); (c) pregnancy morbidity (pre-fetal death, fetal death, and pre-eclampsia and placental insufficiency with severe features); (d) cardiac valve disease (thickening or vegetation); and (e) thrombocytopenia. Laboratory domain items defined were coagulation-based functional assay (lupus anticoagulant) and solid phase-based assays (anticardiolipin antibody IgG/M and anti-β2-Glycoportein-I antibody IgG/M). Based on comprehensive literature review and Steering Committee consensus, we defined and structured APS clinical and laboratory domains. Preliminary definitions were subsequently evaluated and confirmed in late Phase III using the derivation cohort and multicriteria decision analysis prior to validation the 2023 ACR/EULAR APS Classification Criteria.
The clinical significance of acquired resistance to activated protein C (APCr) and antibodies against protein C (anti-PC) in antiphospholipid syndrome (APS) has not been established. This study sought to determine the prevalence of APCr and anti-PC, associations with aPL profile and clinical phenotypes, and exploratory associations with subsequent thrombosis. Three-hundred and seventy patients persistently positive for antiphospholipid antibodies (aPL) with/without APS (aPL-only (n = 77), pregnancy morbidity (PM, n = 43), venous thromboembolism (VTE, n = 132), arterial thrombosis (AT, n = 87), or VTE+AT (n = 31) and 51 healthy controls were studied. Baseline APCr was determined using thrombin generation with recombinant human APC (rhAPC) or Protac®. Anti-PC and avidity were detected by in-house ELISA. All patient subgroups had markedly greater APCr compared to healthy controls (p < 0.001), with greatest APCr observed in VTE+AT or triple aPL-positive patients. Anti-PC were present in 42% of patients, with VTE+AT exhibiting significantly higher prevalence of high avidity anti-PC (79%) compared to aPL-only patients (38%) (p < 0.05). During prospective follow-up of 283 patients from the APS ACTION Registry (median 8.3 years), 25/283 (8.8%) had new thrombosis, with similar incidence between patients with or without APCr or anti-PC (p > 0.60). Non-anticoagulated patients with APCr had more thrombotic events compared to those without, although not statistically significant (HR 4.5, 95% CI 0.8-25.9, p = 0.14). High prevalence of APCr was seen across all aPL-positive patients, strongly associated with high avidity anti-PC. Lack of association with thrombosis may reflect confounding by baseline anticoagulation and limited events. The association of APCr with thrombosis in non-anticoagulated patients merits further exploration.
BackgroundCatastrophic Antiphospholipid Syndrome (CAPS) is a rare but highly severe manifestation of antiphospholipid syndrome (APS), occurring in fewer than 1% of APS patients, but is associated with mortality of around 25-37%, despite treatment. It is characterized by rapid onset of widespread thrombotic events leading to microangiopathy, intravascular thrombosis with multiorgan failure, involving three or more organs within one week. Most published data originate from European or multinational registries like the CAPS Registry. However, data on CAPS in Latin American populations, who may differ in genetic background, socioeconomic status, and healthcare access, remain scarce.MethodsThe objective was to describe the clinical characteristics, treatment strategies, and outcomes of patients diagnosed with CAPS at a tertiary referral center in Mexico City over 5 years. We conducted a retrospective cohort study of patients who fulfilled the CAPS classification criteria between January 2019 and December 2023.ResultsNineteen patients were included (74% female; median age 38.4 years). Six had primary APS, while 11 had concomitant systemic lupus erythematosus (SLE). Based on the 2019 EULAR aPL titers classification, seven patients were classified as low-risk and 12 as high-risk. In 47%, CAPS was the first manifestation of APS. Precipitating factors were identified in 94.7% of cases, most commonly infections and anticoagulant withdrawal. The most frequently affected were the arterial and venous circulation (74% and 68%, respectively), hematologic manifestations (47%), kidneys (42%), lungs (42%), and the heart (32%). Treatment strategies included anticoagulation (84%), corticosteroids (79%), plasma exchange (79%), triple therapy (74%), and, in selected cases, immunosuppressants. Overall mortality was 42%; among survivors, 75% achieved full recovery with no relapses.ConclusionThis study represents one of the largest single-center series of CAPS in a non-Caucasian population. Our findings reveal a predominance of high-risk, secondary APS-mainly
ObjectiveTo evaluate differences in morbidity and mortality between patients with primary antiphospholipid syndrome (PAPS) and APS secondary to systemic lupus erythematosus (SAPS), classified according to the 2023 ACR/EULAR APS criteria.MethodsA single-center retrospective observational study including consecutive adult patients evaluated for suspected APS, retrospectively classified according to the 2023 ACR/EULAR APS criteria. Those patients who were included were categorized as SAPS based on the presence of concomitant SLE, defined using the 2012 Systemic Lupus International Collaborating Clinics criteria. Demographic, clinical, laboratory, and outcome data were extracted from medical records. Group comparisons were performed using t-tests, chi-square or Fisher's exact tests. Multivariable Cox regression was used to identify factors associated with mortality.ResultsOf 432 patients who were screened, 210 (48.6%) fulfilled the 2023 ACR/EULAR criteria and were included, comprising 151 (71.9%) with PAPS and 59 (28.1%) with SAPS. Compared with PAPS, SAPS patients were more frequently female (91.7% vs 65.6%, p < 0.001), of younger age at first APS-related event (34.2 vs 43.1 years, p < 0.001), and had a higher prevalence of renal disease (33. 9% vs 6.0%, p < 0.001). Rates of venous, arterial, recurrent thrombosis, and obstetric manifestations were similar between groups. CAPS and overall mortality were higher in SAPS (11.9% vs 2.7%, p = 0.01; 22.0% vs 10.6%, p = 0.045, respectively). In multivariable Cox regression, increasing age at first event, SAPS, and renal disease were independently associated with increased mortality (adjusted HR 1.1, 5.28, and 3.16, respectively).ConclusionSAPS is associated with higher mortality and increased CAPS risk, emphasizing the adverse prognostic impact of concomitant SLE and the need for tailored risk stratification.
Background: Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are complex autoimmune diseases with the potential to affect multiple organ systems and significantly impact quality of life. In the Middle East and North Africa (MENA), the burden of these conditions is amplified by a combination of genetic predisposition, environmental exposures, and socio-economic factors that shape both presentation and outcomes. High consanguinity rates, high ultraviolet exposure, infections, and lifestyle factors contribute to earlier onset and more aggressive disease, with lupus nephritis affecting up to 60% of patients. APS adds an additional layer of complexity through thrombotic events and pregnancy complications. Purpose: This review brings together current knowledge on the epidemiology, clinical patterns, and management challenges of SLE and APS across the region. Results: While individual country reports exist, the lack of large-scale registries limits our ability to fully define disease prevalence and outcomes. Delayed diagnosis, shortages of rheumatology specialists, and unequal access to advanced diagnostics and biologic therapies remain persistent barriers. In some low-resource or conflict-affected settings, even basic immunosuppressive medications are inconsistently available. The financial impact is substantial, driven by hospitalizations, medications, and loss of productivity, with many patients facing significant out-of-pocket costs. Recent advances, including biologics such as belimumab and anifrolumab, offer opportunities to improve outcomes but are not equitably accessible across the region. Conclusions: Moving forward, investment in healthcare infrastructure, training, and culturally appropriate patient education will be essential. Establishing regional registries, expanding research into genetic and environmental risk factors, and developing locally relevant management strategies are critical next steps. By addressing these gaps through coordinated action between policymakers, healthcare providers, researchers, and patient communities, it is possible to reduce the disparities in care and improve survival, function,
The objective of this review was to assess the clinical efficacy, safety, and immunological effects of biologic therapies in patients with primary APS (pAPS) and catastrophic APS (CAPS). A systematic literature review was performed using PubMed and Embase (January 2005-January 2025), including studies involving adult patients diagnosed with pAPS or CAPS treated with rituximab, eculizumab, belimumab, or daratumumab. Data on clinical features, therapeutic indications, treatment responses, serological changes, and adverse events were extracted and synthesized. Fifty publications, encompassing over 100 patients, were included. Rituximab was the most frequently used biologic therapy and showed substantial efficacy in haematologic and cutaneous manifestations, notably thrombocytopenia and livedoid vasculopathy, though with limited impact on aPL levels. Eculizumab was effective in complement-mediated presentations such as thrombotic microangiopathy (TMA), thrombocytopenia, and renal involvement, with minimal serological changes. Belimumab led to both clinical and serologic improvement in select high-risk individuals. Daratumumab, reported in a single refractory case, temporarily reduced aPL titres, suggesting potential benefit from plasma cell-targeted approaches. Biologic therapies may represent valuable adjunctive options for specific APS phenotypes, especially refractory or complement-driven cases. However, the data remain limited by the heterogeneity in patient populations, the absence of standardized disease activity metrics, and unclear definitions of treatment response. Future studies should prioritize multicentre prospective designs, standardized outcome measures, and biomarker-driven stratification to guide personalized use of biologics in APS.
IgM aCL and anti-β2 glycoprotein I (aβ2GPI) positivity have been downgraded in the current classification criteria for APS. We assessed the clinical relevance of IgM aPL in APS. A 5-year longitudinal study was conducted in 186 individuals: 54 aPL carriers, 83 with thrombotic APS (TAPS), and 49 with obstetric APS (OAPS). Patient enrolment was based on the Sydney classification criteria. aPL thresholds for the chemiluminescence immunoassay and ELISA were established using a cohort of 250 healthy donors. In the APS cohort (n = 132), at the time of patient enrolment, 23.5% (31/132) and 37.1% (49/132) of patients were positive for aβ2GPI and aCL, respectively. IgM-only positivity was observed in 45.2% (14/31) of aβ2GPI-positive patients and in 38.8% (19/49) of those positive for aCL. Isotype switching from IgM to IgG occurred in 28.6% (4/14) of aβ2GPI IgM-only positive patients and in 10.5% (2/19) of aCL IgM-only positive patients. The time interval to IgG isotype switching exceeded 3 years for both aPL specificities. IgM aPL prevalence was significantly higher in OAPS than in TAPS [47% (23/49) vs 19% (16/83), P = 0.0014), but similar between aPL-carriers and APS patients [22% (12/54) vs 30% (39/132), P = 0.37]. Importantly, 8% (11/132) of APS patients were positive only for IgM aPL, of whom 82% (9/11) had OAPS with a history of severe preeclampsia or placental insufficiency. The number of mature B cells in APS patients was comparable between aCL/aβ2GPI IgM-only-positive and aCL/aβ2GPI IgG-only-positive patients. Relying solely on IgG may underclassify patients with APS.
To establish the predictive value of antiphospholipid antibody (aPL) negativization on recurrent thrombosis in thrombotic antiphospholipid syndrome (APS). Retrospective cohort study including all consecutive adult patients with APS followed at Hospital de Santa Maria, Lisbon, Portugal, up to December 2024. At diagnosis, all patients were positive for solid-phase aPL. Then, patients were categorized in two groups according to aPL during follow-up: (i) persistently aPL-positive; (ii) aPL-negativization defined as previous aPL-positive and current aPL-negative (two consecutive times, ≥12 months apart). Outcomes included recurrent thrombosis under antithrombotic therapy. Predictors of aPL-negativization and recurrent thrombosis were assessed using Cox regression analysis. Of the 116 included patients (female, 78.4%; primary APS, 72.1%; triple positivity, 40.5%), totalling 1084 patient years (PY), 31.9% became aPL-negative (3.4 events/100PY). The follow-up time was similar between aPL-positive and aPL-negativization groups (P = 0.681), and before and after aPL-negativization (P = 0.072). At diagnosis, triple aPL-positivity predicted against aPL-negativization, while primary APS predicted aPL-negativization. Forty-five patients (38.8%) experienced 68 recurrences (4.2 events/100PY). Age at APS onset, arterial thrombosis and persistent triple aPL-positivity predicted recurrence. Globally, aPL-negativization did not predict recurrence (HR 0.58, 95%CI 0.29-1.14). Among patients who became aPL-negative, the cumulative incidence of recurrent thrombosis did not differ before aPL-negativization (HR 0.52, 95%CI 0.26-1.06) but dropped by 88% after aPL-negativization (HR 0.12, 95%CI 0.05-0.58), even after adjusting for age, primary APS and type of initial thrombosis (P = 0.006). The risk of recurrent thrombosis drops significantly after aPL-negativization, highlighting the utility of serial aPL monitoring in clinical practice.
Autoimmune heparin-induced thrombocytopenia (aHIT) represents a severe variant of immune-mediated thrombocytopenias (IMTs) in which anti-platelet factor 4 (PF4) antibodies activate platelets independently of heparin, leading to both thrombosis and thrombocytopenia. Despite its clinical significance, aHIT remains poorly understood and lacks evidence-based immunomodulatory treatments. This narrative translational review integrates mechanistic and therapeutic insights from immune thrombocytopenia (ITP) and antiphospholipid syndrome (APS) to identify shared pathogenic pathways relevant to aHIT. Literature from 2015 to 2025 was analyzed across PubMed, Scopus, Web of Science, and ClinicalTrials.gov, focusing on FcγRIIa-Syk-BTK signaling and complement activation as central drivers of platelet activation and clearance. Preclinical and clinical data indicate that targeting these axes with Syk inhibitors (fostamatinib), BTK inhibitors (rilzabrutinib, zanubrutinib), and complement inhibitors (sutimlimab) can restore platelet counts and mitigate immune-driven thrombosis. These findings underscore the therapeutic potential of pathway-specific interventions in aHIT, highlighting the need for biomarker-guided, translational trials to validate their efficacy and safety. Bridging mechanistic evidence from ITP and APS provides a framework for precision immunotherapy in autoimmune HIT.
This study aimed to evaluate the prevalence of hyposplenism in patients with systemic lupus erythematosus (SLE) and its association with an increased risk of infection. This single-centre study included patients with SLE who underwent a systematic evaluation for Howell-Jolly bodies (HJB) on peripheral blood smear, a marker of hyposplenism. Patients exhibiting HJB were classified as having hyposplenism (cases), whereas those without such inclusions were considered to have normal splenic function (controls). We collected radiological data to assess spleen morphology. The prevalence of infections and thrombosis was recorded. In a tertiary care cohort of 245 patients, 23 (9.4%) demonstrated HJB on peripheral smear, after exclusion of those with a history of splenectomy or intrinsic haemolytic anaemia. In multivariable analysis, three factors were independently associated with hyposplenism: paediatric-onset SLE (OR 5.2, 95% CI 1.3 to 21.2, p=0.02), antiphospholipid syndrome (OR 6.8, 95% CI 2.2 to 20.8, p=0.001) and history of constitutional symptoms of SLE (OR 3.9, 95% CI 1.2 to 12.4, p=0.02). Patients with HJB had a higher risk of infection-related hospitalisation (OR 7.3, 95% CI 2.4 to 21.8, p<0.001), particularly pneumococcal infections (5/23 cases (21.7%) vs 1/222 controls (0.5%), p<0.001), but no increased risk of thrombosis (OR 1.6, 95% CI 0.3 to 7.8, p=0.57). Hyposplenism was associated with splenic hypoplasia identified on abdominal CT scan (6/23 assessed cases (26%) vs 0/166 assessed controls (0%), p<0.001), but not with splenic calcifications. Hyposplenism was also associated with eosinophilia, neutrophilia, monocytosis and thrombocytosis. Hyposplenism was observed in 9.4% of patients with SLE in a tertiary care cohort and was significantly associated with an increased risk of infection and radiological splenic hypoplasia. These findings highlight the importance of preventive measures for impaired splenic function, including patient and physician education, vaccination
The diagnosis of antiphospholipid syndrome (APS) uses standard antibodies (lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) IgG/IgM, β2-glycoprotein I antibodies (β2GPI) IgG/IgM), which results in some patients with 'seronegative APS' being overlooked. The diagnostic value of an extended antibody profile, including antiphosphatidylserine/prothrombin complex (aPS/PT) and aCL/β2GPI IgA, requires clarification. This study aimed to define antibody heterogeneity in APS and determine the diagnostic and risk-stratification value of novel antibodies. We retrospectively enrolled 2994 patients with clinical features suggestive of APS who underwent testing for criteria antibodies (LAC, aCL IgG/IgM and β2GPI IgG/IgM) and extended markers (aPS/PT IgG/IgM and aCL/β2GPI IgA). Principal component analysis (PCA) explored antibody reactivity patterns. Multivariate logistic regression identified independent diagnostic predictors, and receiver operating characteristic curve analysis evaluated diagnostic performance. Associations between antibodies and clinical parameters defined clinical phenotypes. PCA revealed three dimensions explaining 73.56% of variance: principal component (PC)1 (IgG/LAC axis; 41.42%), PC2 (specific IgM axis; 18.12%) and PC3 (specific IgA axis; 14.02%). aPS/PT-IgM was a strong independent predictor of clinical diagnosis (adjusted OR 1.147, 95% CI 1.129 to 1.165, p<0.001). The area under the curve for diagnosing triple-negative APS was 0.868 for aPS/PT-IgM. Standard criteria antibodies lost independent significance in the full model. Phenotypic analysis identified three subtypes: a 'classical type' (PC1-High) with prolonged coagulation times and complement consumption; an 'inflammatory type' (PC3-High) with elevated systemic inflammation markers without complement consumption; and a 'restricted type' (PC2-High) associated with anaemia. Distinct antiphospholipid antibody heterogeneity exists, categorisable into 'classical', 'inflammatory' and 'restricted' subtypes. This study identifies aPS/PT-IgM as a strong independent serological marker associated with clinical status. Incorporating aPS/PT-IgM into routine testing could significantly reduce seronegative APS misdiagnosis.
Diffuse alveolar haemorrhage (DAH) is a rare and poorly understood manifestation of antiphospholipid (AP) syndrome (APS). This study describes the clinical presentation, treatment and prognosis of DAH in APS with or without catastrophic APS (CAPS). A retrospective multicentre French study includes all APS patients diagnosed according to the Sydney criteria with a history of definite DAH. Of the 26 patients included, 15 (58%) were female (median age, 45.5 years; 95% CI, 35-58.1); 23 (88%) patients had a history of thrombotic events (6 arterial), and 13 (50%) had CAPS. Twenty (77%) were triple-positive for APL antibodies, 5 (19%) had systemic lupus erythematosus, and DAH was inaugural for 7 (27%) patients. Twenty-two patients (85%) were treated with anticoagulants, 22 (85%) with steroids and 8 (31%) with immunosuppressive therapy. Complete remission was achieved in 18 (69%) cases. DAH relapses occurred in 14 patients (54%) after a median of 1.8 (95% CI 1.1-3.6) years. Risk factors for DAH relapse were histories of arterial thrombosis (hazard ratio (HR) 4.6, 95% CI 1.2-17), transient ischaemic attack or stroke (HR 7.8, 95% CI 2.2-28), mechanical ventilation during DAH episode (HR 6.1, 95% CI 0.99-37) and triple APL positivity. Multivariate analysis showed a higher risk of DAH relapse in patients without (vs with) CAPS (HR 6.8, 95% CI 1.0-45.3; P = 0.048). Overall mortality was higher in patients with CAPS (7.7% at 1 year and 37.1% at 5 years); no patients without CAPS died. The immediate prognosis of DAH, mainly treated with anticoagulants and steroids, was good. Patients with CAPS had a higher mortality rate in the long-term follow-up. Triple-positive and/or arterial phenotype patients more frequently experienced DAH relapses even when treated with anticoagulants.
To characterize the clinical and serological correlates of cardiovascular magnetic resonance (CMR)-confirmed myocarditis in idiopathic inflammatory myopathies (IIM), evaluate the diagnostic performance of high-sensitivity cardiac troponin I (hs-TnI), and quantify the independent prognostic impact of myocarditis relative to interstitial lung disease (ILD). Single-center retrospective cohort study (STROBE-compliant) of 142 consecutive adults with IIM (2019-2025). Myocarditis was confirmed by CMR according to the 2018 Lake Louise Criteria, performed both at diagnosis and during follow-up (with or without immunosuppression) upon clinical suspicion and/or elevated hs-TnI. Myositis-specific antibodies (MSA), myositis-associated antibodies (MAA), anti-Ro52 and antiphospholipid antibodies (aPL, Sydney criteria: ≥40 GPL/MPL units confirmed at ≥ 12 weeks) were systematically recorded. Associations were assessed with Fisher's exact test and logistic regression; multivariable models were pre-specified as parsimonious (two predictors) given the limited event count. Overall survival was analyzed with Kaplan-Meier curves, the log-rank test and Cox proportional-hazards regression. Myocarditis was confirmed in 9/142 patients (6.3%), without significant association with IIM class (P = 0.303) or with the antisynthetase antibody subgroup (anti-Jo-1 + PL-12 + PL-7 + EJ; 5.8% vs. 6.7%, P = 1.000). In univariable analyses, myocarditis was associated with Raynaud phenomenon (OR 13.6, 95% CI 2.3-80.0), aPL positivity (OR 10.7, 95% CI 2.6-43.9), anti-Ro52 coexisting with MSA/MAA (OR 8.7, 95% CI 2.2-34.8), anti-PM/Scl (OR 7.1, 95% CI 1.6-30.3), fever (OR 7.1, 95% CI 1.6-30.3) and ILD (OR 4.7, 95% CI 1.1-20.3). hs-TnI was markedly higher in myocarditis (median 366 vs. 3.5 ng/L; P < 0.001) with an area under the receiver-operating characteristic curve (AUROC) of 0.91 (95% CI 0.83-0.98). In the event-constrained multivariable model, Raynaud phenomenon (adjusted OR 13.1, 95% CI 1.5-112.7) and aPL (adjusted OR 7.2, 95% CI 1.4-36.0) remained independently associated. All-cause mortality was higher in myocarditis (44% vs. 9%; OR 7.95, 95% CI
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that predominantly affects women of childbearing age. As the prevalence of SLE rises, and advances since the 1960s have substantially improved survival and quality of life, the number of women with SLE who become pregnant is steadily increasing. Although pregnancy is feasible for most patients with well-controlled SLE, pregnancy remains challenging for both women with SLE and clinicians because the risk of maternal complications and adverse fetal outcomes is higher than that in the general population. Moreover, the increased risk of pregnancy complications persists in subsequent pregnancies in women with SLE, whereas in healthy women this risk decreases owing to the development of maternal-fetal immune tolerance. During pregnancy and the postpartum period, women remain at risk of disease flares and other complications, particularly those with active disease at conception, a history of lupus nephritis, antiphospholipid syndrome or recent medication withdrawal. Important knowledge gaps persist regarding the mechanisms underlying these complications and the safety of treatment during conception, pregnancy and lactation. Preconception counselling, assessment of risk factors for adverse outcomes, pregnancy planning, timely medication adjustment and multidisciplinary management are essential to improve the maternal and fetal outcomes in women with SLE.
To compare immune cell subsets and interferon (IFN) expression in placentas from patients with systemic lupus erythematosus (SLE), primary Sjögren's disease (pSjD), antiphospholipid syndrome (APS), healthy controls (HC) and of women with adverse pregnancy outcomes (APO) without these systemic rheumatic diseases (SRD). Placenta biopsies from HC, SLE, pSjD, APS, and patients with fetal growth restriction (FGR), spontaneous preterm birth (PTB), or FGR and preeclampsia (FGR/PE) attended between 2008 and 2022 were recovered from the pathology biobank of the University Medical Center Groningen. Clinical characteristics and APO were retrieved from medical records. Immunohistochemistry was performed for Myxovirus resistance protein 1 (MxA), CD3, CD20, CD56, CD68, CD123, and Foxp3. The proportion of positive cells was established using an automated detection classifier, while MxA expression was assessed semi/quantitatively discriminating between maternal (decidua) and fetal (villi) tissue. Finally, placental lesion classification was performed. Our study included placentas from 11 SLE, 4 pSjD, 8 APS, 4 PTB, 8 FGR, 8 FGR/PE patients and 11 HC. A high rate of APO (70%) was identified in SRD patients. Patients with SRD had a higher macrophage (CD68+) count in decidua and villi than HC, but no differences were observed in T (CD3+), B (CD20+), NK (CD56+) and T regulatory (Foxp3+) cell count. No plasmacytoid dendritic cells (CD123+) were identified. Furthermore, patients with these SRD had higher MxA values than HC in villi but not in decidua. SLE, pSjD and APS patients have an increased macrophage count and interferon upregulation in the placenta compared to HC. Therefore, a pro-inflammatory environment might be key inducing placental dysfunction, which may lead to subsequent APO development.
Mixed connective tissue disease (MCTD) has long been debated as an early nonspecific phase/symptom of differentiated connective tissue diseases (dCTD), similarly to interstitial pneumonia with autoimmune features (IPAF) and very early diagnosis of systemic sclerosis (SSc) (VEDOSS). We aimed to evaluate the predictive value of IPAF, VEDOSS and dCTD classification criteria variables in MCTD patients. We conducted an observational study within the French MCTD cohort. IPAF, VEDOSS and current dCTD classification criteria were used to classify patients. Three hundred and twenty-four MCTD patients were included and followed for 8 (3.3-13) years. Among them, 111 (34.3%) progressed into a dCTD, that is, 50 (15.4%) SSc, 40 (12.3%) systemic lupus erythematosus (SLE) and 11 (3.4%) Sjögren's disease. At diagnosis, 38 (11.7%) patients fulfilled IPAF criteria, among which 15 (39.5%) progressed into a dCTD (vs 75 (26.2%) in patients who did not fulfil IPAF criteria; p=0.09). At diagnosis, 293 (90.4%) patients fulfilled VEDOSS criteria but did not progress significantly more frequently to SSc than MCTD patients without VEDOSS criteria (46 (15.7%) vs 4 (12.9%); p=0.8). At baseline, SSc classification criteria did not predict evolution toward SSc, whereas antiphospholipid antibodies and low C3 and/or C4 were predictive of an evolution toward SLE (p=0.01 and p=0.04, respectively). At MCTD diagnosis, fulfilment of IPAF and/or VEDOSS criteria was not predictive of evolution toward SSc, whereas antiphospholipid antibodies and low C3 and/or C4 were predictive of an evolution toward SLE. This suggests that MCTD patients should be excluded from IPAF and VEDOSS.
This study examined maternal cardiovascular (CV) events relative to adverse pregnancy outcomes (APOs) among individuals with autoimmune rheumatic diseases (ARDs), primary antiphospholipid syndrome (APS), and those with neither. Using a California population-based birth cohort (2005-2020), we identified those with CV events (CVEs), ARDs, and APS through International Classification of Diseases, 9th and 10th revisions, Clinical Modification codes in maternal discharge records. Selected APOs identified from birth certificates were preterm birth (PTB; < 37 weeks' gestation), small-for-gestational-age infants (SGA; birth weight < 10th percentile for age and sex), and a composite of either outcome. Adjusted risk ratios (aRRs) for adverse outcomes and their 95% CIs were calculated. CVEs occurred more frequently in individuals with ARDs (265 of 19,340 [1.4%]) and primary APS (428 of 7758 [5.5%]) than those without (17,130 of 7,004,334 [0.3%]). The presence vs absence of CVEs was associated with a greater incidence of adverse outcomes in ARD (53.2% vs 26.6%), APS (30.6% vs 20.7%), and non-ARD/APS pregnancies (28.2% vs 15.2%). CVEs were associated with increased risks of SGA in all groups (aRRs 1.2-1.5) and PTB in ARD (aRR 1.6, 95% CI 1.3-2.0) and non-ARD/APS (aRR 1.7, 95% CI 1.7-1.8) pregnancies. CVEs were associated with modestly increased risks (20-70%) for PTB, SGA, or both across the groups. Notably, > 50% of ARD pregnancies with CVEs experienced APOs. Given that ARD and APS pregnancies have higher (although still low) rates of CVEs and have higher baseline risks of APOs than the general population, the additional burden conferred by CVEs is clinically important.
Antiphospholipid syndrome (APS) is an autoimmune disease characterised by obstetric morbidity and recurrent venous and/or arterial thrombosis. It is frequently associated with systemic lupus erythematosus, and thrombocytopenia is a common manifestation. This study aimed to compare patients with APS, with and without thrombocytopenia, and to describe management and outcomes of severe thrombocytopenia. We performed a retrospective single-centre study that included 432 patients with APS. Patients were divided into three groups according to the platelet count nadir: severe thrombocytopenia (< 50 G/L), moderate thrombocytopenia (between 50 and 130 G/L) and no thrombocytopenia (≥ 130 G/L). 142 patients developed thrombocytopenia during follow-up (32.9%): 57 (13%) had severe thrombocytopenia (< 50 G/L) and 85 (19.4%) had moderate thrombocytopenia (50-130 G/L). Patients with thrombocytopenia more frequently experienced thrombotic manifestations, including lower limb deep vein thrombosis (49% vs 37%, p=0.014), coronary thrombosis (15% vs 6.6%, p=0.006) and catastrophic antiphospholipid syndrome (CAPS) (27% vs 2.1%, p<0.001). Thrombocytopenia was more frequently associated with pre-eclampsia (16.8% vs 3.7%, p<0.001) and other APS manifestations, including skin (ulcer 4.9% vs 1.4%, p=0.046, cutaneous necrosis 7% vs 0.7%, p<0.001), cardiovascular (MINOCA 7% vs 0.7%, p<0.001, valvular disease 19.7% vs 9.3%, p=0.002), renal (18.3% vs 3.1%, p<0.001) and pulmonary (5.6% vs 1%, p=0.007) manifestations. Aetiologies of severe thrombocytopenia were mainly immune thrombocytopenia (ITP) and CAPS. In patients with severe thrombocytopenia, treatment followed the approach used for primary ITP, and anticoagulation was generally maintained even in the presence of bleeding episodes. Overall survival was poorer in patients with severe thrombocytopenia (p<0.0001). Our results suggest that thrombocytopenia is associated with a more severe APS phenotype and increased mortality.